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New Gene Tied to Deadly Ovarian Cancer

Two research teams have linked an unexpected gene to an aggressive
and hard-to-treat form of ovarian cancer.

Microscopic view of the ovary showing the
central egg surrounded by protective layers of cells. Image
by Ivor Mason, King's College London. All rights reserved by
Wellcome Images.

Ovarian cancer is the fifth deadliest cancer among women nationwide.
The subtype known as ovarian clear cell carcinoma is poorly understood
and can be especially resistant to standard therapy. To learn more
about the genetic origins of ovarian clear cell carcinoma, 2 independent
teams of scientists used different techniques to examine the exons,
or protein-coding regions of the genome, in ovarian tumor cells.

The first study, supported in part by NIH's National Cancer Institute
(NCI), evaluated both tumor and normal cells from 8 patients who
had ovarian clear cell carcinoma. A research team led by Dr. Nickolas
Papadopoulos of Johns Hopkins Kimmel Cancer Center sequenced all
18,000 protein-coding genes from the cells and identified 4 that
were mutated in at least 2 tumors but not in the normal cells.
Of these, the most common was the gene ARID1A, which had
never before been linked to ovarian cancer.

The scientists then sequenced the 4 implicated genes in normal
and tumor cells from an additional 34 patients. Most of the tumor
samples had mutations in ARID1A (57% of the 42 tumors).
Two other genes that had previously been tied to ovarian cancer—PIK3CA and KRAS—were
found in 40% and 5% of the tumors, respectively. The fourth gene, PPP2R1A,
hadn't previously been associated with ovarian cancer. It was found
in 7% of the tumors.

As reported in the early online issue of Science on September
8, 2010, the researchers conclude that ARID1A must act
as a tumor suppressor gene. Its protein product is known to play
a role in chromatin remodeling, which is a process that changes
how DNA is packaged in the cell's nucleus. Chromatin remodeling
can affect how and when certain genes are transcribed. When ARID1A is
mutated, genes may be incorrectly switched on or off, which can
cause cells to grow and flourish unchecked.

In the second study, published that same day in the New England
Journal of Medicine, a Canada-based research team led by
Dr. David Huntsman took a slightly different approach. Rather
than sequencing protein-coding DNA regions, they sequenced the
transcriptome—the complete set of expressed RNAs. They
analyzed different types of tumors from several tumor banks,
including an NCI-funded bank at Johns Hopkins. The scientists
found that the ARID1A gene was mutated in 46% (55 out
of 119) of ovarian clear cell tumors and in 30% (10 out of 33)
of endometrioid ovarian tumors, a different subtype of ovarian
cancer. In contrast, the gene wasn’t altered in any of
the 76 samples of a different type of ovarian tumor.

Both ovarian clear cell cancer and endometrioid cancer can arise
from endometriosis, a condition in which cells from the uterine
lining migrate and grow in other locations, such as the ovaries.
The scientists say their findings may help to shed light on molecular
events that transform endometriosis into ovarian cancer.

"The interesting thing about this gene [ARID1A]
is that it's tied to something called epigenetic changes, which
include changes in how the DNA is packed and regulated," says
Papadopoulos. Epigenetic factors affect gene activity—in
this case by altering chromatin—without altering the DNA
sequence. "The next step will be to understand this pathway
better," he says.